Implants for localized drug delivery and methods of use thereof

ABSTRACT

Provided herein is an implant for delivering a hydrophobic active agent to a target tissue. The implant may include a scaffold defining a first surface and a second surface opposite the first surface, wherein the scaffold is substantially impermeable to the hydrophobic active agent, and a silicone tubing having a wall permeable to the hydrophobic active agent, wherein a first length of the silicone tubing is affixed to the first surface of the scaffold, wherein two ends of the silicone tubing extend from the first surface, and wherein a path outlined by a second length of the silicone tubing within the first length is circuitous. Also provided is a method of using the implant to locally deliver the hydrophobic active agent to the target tissue, and kits that find use in performing the present method.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/502,742, filed on Feb. 8, 2017, which is a 371 of InternationalApplication Serial No. PCT/US2015/045687, filed on Aug. 18, 2015, whichclaims the benefit of U.S. Provisional Patent Application No.62/039,302, filed Aug. 19, 2014, which application is incorporatedherein by reference in its entirety.

BACKGROUND

Reservoir-based systems for drug delivery provide a way to deliver drugsto a patient using passive or active mechanisms, and include oral,dermal and implantable systems. Passive systems utilize diffusion,osmotic potential, or concentration gradients as their driving forces,while active systems include mechanical pumping, electrolysis, and otheractuation methods. Reservoir-based implants can be used for bothsystemic and targeted drug delivery applications.

Breast cancer is the most common cancer diagnosed in US women, and thesecond leading cause of death from cancer in US women. Over 200,000women are diagnosed with breast cancer each year in the United States,and 5-10% of these are related to hereditary mutations such as the BRCA1 and 2 gene mutations. The treatments for these women include surgicalremoval of the breasts or systemic pharmacologic estrogen withdrawal,such as through systemically delivered antiestrogens.

The burden of suffering from prostate cancer in the United States issignificant. In 2009, approximately 192,000 men were diagnosed withprostate cancer, and 27,000 men were expected to die from this disease.Approximately 2.2 million living American men have been diagnosed withprostate cancer, and some are living with metastatic disease, a painfuland functionally limiting stage of the disease. Prostate cancer is byfar the most commonly diagnosed cancer among American men and remainsthe second leading cause of cancer death in men. Hormonal therapy ofprostate cancer includes a wide variety of treatments designed to affectcells whose normal functioning depends on androgens, which includetestosterone and dihydrotestosterone, among others. Prostate cancercells are generally very susceptible to treatments that lower androgenlevels or affect the normal action of these hormones.

SUMMARY

Provided herein is an implant for delivering a hydrophobic active agentto a target tissue. The implant may include a scaffold defining a firstsurface and a second surface opposite the first surface, wherein thescaffold is substantially impermeable to a hydrophobic active agent, anda silicone tubing having a wall permeable to the active agent, wherein alength of the silicone tubing is affixed to the first surface of thescaffold, wherein the two ends of the silicone tubing extend from thefirst surface, and wherein a path outlined by a second length of thetubing within the first length is circuitous. Also provided is a methodof using the implant to locally deliver a hydrophobic active agent to atarget tissue, and kits that find use in performing the present method.In some embodiments, the silicone tubing is SILASTIC tubing.

In any embodiment, the implant may define a first, second and thirdorthogonal dimensions, and wherein the length of the silicon tubing islonger than the longest dimension of the first, second and thirdorthogonal dimensions.

In any embodiment, the circuitous path may include one or moreswitchbacks on the first surface of the scaffold. In some embodiments,the circuitous path includes a spiral pattern.

In any embodiment, the first length of the silicone tubing may overlie30% or more of the first surface of the scaffold.

In any embodiment, an amount of liquid introduced into the implant fromthe first end of the silicone tubing under sufficient pressure advancesthrough the tubing to reach the second end when a volume of liquid inthe implant approximately equal to an internal volume of the siliconetubing between the first and second ends is displaced by the appliedpressure.

In any embodiment, the scaffold is substantially planar.

In any embodiment, the scaffold may be a polymeric scaffold.

In any embodiment, the silicone tubing includes an amount of the activeagent sufficient to deliver a therapeutically effective amount of theactive agent to the target tissue. In some embodiments, the wall of thesilicone tubing includes an amount of the active agent sufficient todeliver a therapeutically effective amount of the active agent to thetarget tissue. In some cases, the silicone tubing includes the activeagent in an amount sufficient to achieve sustained delivery of theactive agent into the target tissue.

In any embodiment, the active agent is a steroid. In some cases, thesteroid is cholesterol, estradiol, progesterone, testosterone, orderivatives or synthetic analogs thereof. In some embodiments, thesteroid is an anti-estrogen. In some cases, the anti-estrogen isfulvestrant.

In any embodiment, the implant may include one of more suture tabs.

In any embodiment, the implant may further include one or more fillports attached to the first and second ends of the silicone tubing. Insome cases, the implant includes a fill port containing a first chamberin fluid communication at the fill port with the first end of thesilicone tubing, and a second chamber in fluid communication at the fillport with the second end of the silicone tubing. In some embodiments,the fill port includes an imageable backing. In certain embodiments, thefill port includes one or more suture tabs.

Also provided herein is a method of delivering a hydrophobic activeagent to a target tissue in a subject, the method including the step ofimplanting an implant of any of the embodiments disclosed above in atarget tissue, in a manner sufficient to locally deliver atherapeutically effective amount of a hydrophobic active agent into thetarget tissue, wherein the implanted implant includes the active agent.In some embodiments, the hydrophobic active agent is substantiallyundetectable in the non-target tissue after implanting the implant. Incertain embodiments, the hydrophobic active agent is substantiallyundetectable in a non-target tissue for one week or more afterimplanting the implant. In some cases, the non-target tissue includescirculating blood. In certain embodiments, the subject is a subjectdiagnosed as having or being predisposed to having cancer. In certaincases, the target tissue comprises breast, prostate, uterine, brain,skin, ovarian, gastrointestinal, bladder, muscle, liver, kidney orpancreatic tissue. In some embodiments, the implanting includes changingthe configuration of the implant into a delivery configuration,positioning the implant in the delivery configuration into the tissue,and changing the configuration of the positioned implant into afunctional configuration. In some cases, the silicone tubing in theimplanted implant includes the hydrophobic active agent in dry or liquidform. In some cases, the hydrophobic active agent in liquid form is inan organic solvent.

In any embodiment, the method may further include loading the siliconetubing with the hydrophobic active agent. In some cases, the loadingincludes introducing a solution containing the hydrophobic active agentinto a first end of the silicone tubing, and applying pressure to thesolution in the tubing in a manner sufficient to advance the solutionthrough the silicone tubing to the second end. In some cases, theloading is performed after implanting. In some cases, the methodincludes loading the silicone tubing with a first hydrophobic activeagent before implanting, and loading the silicone tubing with a secondhydrophobic active agent after implanting.

In any embodiment, the method may further include removing thehydrophobic active agent from the silicone tubing after implanting.

Also provided herein is an implant for delivering a hydrophobic activeagent to a target tissue, the implant containing a depot for holding thehydrophobic active agent, wherein the depot includes a silicone tubingdefining a first end and a second end distal to the first end, whereinthe silicone tubing includes a wall permeable to the active agent, andthe silicone tubing includes a switchback, wherein the switchback andthe first end define a first length of the tubing, and the switchbackand the second end define a second length of the tubing, and wherein thefirst and second lengths are intertwined with each other substantiallyalong their respective lengths. In some cases, an amount of liquidintroduced into the implant from the first end under sufficient pressureadvances through the tubing to reach the second end when a volume ofliquid in the implant approximately equal to an internal volume of thesilicone tubing between the first and second ends is displaced by theapplied pressure.

Kits that include an implant of the present disclosure and that find usein implementing the present method are also provided.

BRIEF DESCRIPTION OF THE FIGURES

The skilled artisan will understand that the drawings, described below,are for illustration purposes only. The drawings are not intended tolimit the scope of the present teachings in any way.

FIGS. 1A-C are illustrations showing an implant for active agentdelivery, according to embodiments of the present disclosure.

FIGS. 2A-B are illustrations showing an implant for active agentdelivery, according to embodiments of the present disclosure.

FIG. 3 is an illustration showing an implant for active agent delivery,according to embodiments of the present disclosure.

FIG. 4 is an illustration showing an implant for active agent delivery,according to embodiments of the present disclosure.

FIG. 5 is an illustration showing an implant for active agent delivery,according to embodiments of the present disclosure.

FIG. 6 is an illustration showing an implant for active agent delivery,according to embodiments of the present disclosure.

FIG. 7 is an illustration showing an implant for active agent delivery,according to embodiments of the present disclosure.

FIG. 8 is an illustration showing an implant for active agent delivery,according to embodiments of the present disclosure.

FIG. 9 is an illustration showing an implant for active agent delivery,according to embodiments of the present disclosure.

FIGS. 10A-B are illustrations showing a fill port for use in an implantfor active agent delivery, according to embodiments of the presentdisclosure.

FIGS. 11A-C are schematic illustrations showing a method of loading animplant for active agent delivery, according to embodiments of thepresent disclosure.

FIG. 12 is a schematic diagram showing an implant for active agentdelivery implanted in a target tissue in situ, according to embodimentsof the present disclosure.

FIGS. 13A-B are illustrations showing an implant for active agentdelivery implanted in a breast tissue, according to embodiments of thepresent disclosure.

FIGS. 14A-D are illustrations showing various configurations of animplant for active agent delivery, according to embodiments of thepresent disclosure.

FIG. 15 is an illustration showing an implant for active agent deliveryimplanted in a prostate tissue, according to embodiments of the presentdisclosure.

FIG. 16, panels A and B, is a collection of graphs showing the measuredactivity of fulvestrant eluted into media from a fulvestrant-loadedSilastic® tubing, according to embodiments of the present disclosure.

FIG. 17 is an image showing the activity of fulvestrant eluted intomedia from a fulvestrant-loaded Silastic® tubing, according toembodiments of the present disclosure.

FIG. 18 is a collection of images showing the activity of fulvestranteluted into media from a fulvestrant-loaded Silastic® tubing, accordingto embodiments of the present disclosure.

FIG. 19 is a graph showing measured amounts of fulvestrant eluted intomedia from a fulvestrant-loaded Silastic® tubing, according toembodiments of the present disclosure.

FIG. 20 is a graph showing measured amounts of fulvestrant eluted intosaline from a fulvestrant-loaded Silastic® tubing, according toembodiments of the present disclosure.

FIG. 21 is a graph showing amounts of fulvestrant measured in mammarytissue from mice implanted with a fulvestrant-loaded implant in mammarytissue, according to embodiments of the present disclosure.

FIG. 22 shows Table 1, showing amounts of fulvestrant measured in bloodfrom mice implanted with a fulvestrant-loaded implant in mammary tissue,according to embodiments of the present disclosure.

FIG. 23 is a graph showing measured activity of estradiol eluted intomedia from an estradiol-loaded Silastic® tubing, according toembodiments of the present disclosure.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present teachings, some exemplarymethods and materials are now described.

“Subject” refers to any animal, e.g., a mouse, rat, goat, dog, pig,monkey, non-human primate, or a human.

“Biocompatible,” as used herein, refers to a property of a material thatallows for prolonged contact with a tissue in a subject without causingtoxicity or significant damage.

As used herein, the terms “treat,” “treatment,” “treating,” and thelike, refer to obtaining a desired pharmacologic and/or physiologiceffect. The effect may be prophylactic in terms of completely orpartially preventing a disease or symptom thereof and/or may betherapeutic in terms of a partial or complete cure for a disease and/oradverse effect attributable to the disease. “Treatment,” as used herein,covers any treatment of a disease in a subject, particularly in a human,and includes: (a) preventing the disease from occurring in a subjectwhich may be predisposed to the disease but has not yet been diagnosedas having it; (b) inhibiting the disease, i.e., arresting itsdevelopment; and (c) relieving the disease, e.g., causing regression ofthe disease, e.g., to completely or partially remove symptoms of thedisease.

“Active agent” and “drug” are used interchangeably to refer to anychemical compound that can have a therapeutic and/or preventive effectfor a disease when suitably administered to a subject.

“Therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result.

“Target,” as used in reference to a tissue or site, refers to a tissueor location within a subject's body to which an active agent is, or isintended to be, delivered by an implant of the present disclosure. Thetarget tissue can include pathological tissue, e.g., cancerous tissue,that is to be treated by the active agent, or can include tissue whereoccurrence or recurrence of pathology, e.g., cancer, is to be preventedor delayed. A “non-target tissue” may refer to any tissue that is notthe intended target for delivering an active agent using the implant. Insome cases, the non-target tissue is a tissue that is adjacent thetarget tissue. In some cases, the non-target tissue includes asystemically circulating tissue, such as blood.

“Local,” as used in reference to delivery of an active agent to a targettissue, is meant to characterize the distribution of the active agent inthe body of a subject preferentially to the target tissue compared tonon-target tissue. In some cases, the local delivery of the active agentto the target tissue includes the active agent being substantiallyabsent from a non-target tissue.

“Hydrophobic” and “lipophilic” are used interchangeably to refer to aproperty of a compound to dissolve more readily in an organic solvent(e.g., dimethylsulfoxide (DMSO), ethanol, methanol, dimethylformamide(DMF), octanol, castor oil, etc.) compared to an aqueous solution atambient temperature. The hydrophobicity or lipophilicity of thehydrophobic compound, as defined by the distribution coefficient (log D)between water and octanol, may be 4 or higher.

“Tubing,” as used herein refers to an elongated structure having acylindrical wall defining an interior space. A tubing can have asubstantially constant inner diameter along the length of the tubingthat forms the implant. The length of the elongated structure may belonger than the width by a factor of 20 or more.

An “end,” as used in reference to an end of a tubing, is meant toindicate an extremity or an extreme portion of the tubing. The end of atubing does not necessarily refer to a physical termination of thetubing, although the end of the tubing may in some cases coincide with aphysical break in the tubing, depending on context.

The “internal volume,” as used in reference to a tubing, refers to thevolume of the space in the tubing bound by the internal wall.

“Remote,” as used herein, refers to a physically distinct locationrelative to a component of an implant of the present disclosure that is,or is to be, implanted at a target tissue to which an active agent is tobe delivered by the implant.

“Outline,” as used in reference to an outline of an elongated structure,refers to a line representing the elongated structure formed by reducingthe structure to only its longitudinal dimension, e.g., by skeletonizingthe profile of the elongated structure at all points along thestructure.

“Circuitous,” as used herein, refers to a path outlined by a length oftubing not being a straight path. The circuitous outline may form apattern in two or three dimensions. In some cases, a circuitous pathoutlined by a length of tubing may change directions by 180° or more,e.g., 270° or more, 360° or more, 540° or more, including 720° or morebetween two points along the length.

“Orthogonal dimensions,” as used herein, refers to the three independentaxes of three dimensional space, commonly referred to as the x-, y- andz-axes.

A “switchback,” as used in reference to a length of tubing, refers to apattern formed by the length of tubing where the path along the tubingundergoes a turn of about 180° within a short portion of the length oftubing. A switchback in a tubing results in the two sections of thetubing adjacent the switchback being substantially parallel to eachother. The curvature of the switchback, may be substantially higher inmagnitude than the curvature of the two sections of the tubing adjacentthe switchback (i.e., is a local maximum or minimum of curvature),measured in the plane of the two sections of the tubing.

“Unidirectional,” as used in reference to localized delivery of anactive agent to a target tissue, is meant to indicate that the diffusionor migration of the active agent through the tissue is biased in favorof a first direction relative to a surface, e.g., a surface of thescaffold on which a silicone tubing is affixed, compared to a seconddirection relative to the surface that is opposite from the firstdirection.

Before the various embodiments are described, it is to be understoodthat the teachings of this disclosure are not limited to the particularembodiments described, and as such can, of course, vary. It is also tobe understood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present teachings will be limited onlyby the appended claims.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described inany way. While the present teachings are described in conjunction withvarious embodiments, it is not intended that the present teachings belimited to such embodiments. On the contrary, the present teachingsencompass various alternatives, modifications, and equivalents, as willbe appreciated by those of skill in the art.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the present disclosure.

The citation of any publication is for its disclosure prior to thefiling date and should not be construed as an admission that the presentclaims are not entitled to antedate such publication by virtue of priorinvention. Further, the dates of publication provided can be differentfrom the actual publication dates which can need to be independentlyconfirmed.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimscan be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which can be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentteachings. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

One with skill in the art will appreciate that embodiments of thepresent disclosure are not limited in its application to the details ofconstruction, the arrangements of components, category selections,weightings, pre-determined signal limits, or the steps set forth in thedescription or drawings herein. The present disclosure may encompassother embodiments and may be practiced or be carried out in manydifferent ways.

DETAILED DESCRIPTION

As summarized above, the present disclosure provides an implant fordelivering a hydrophobic active agent to a target tissue, the implantincluding a scaffold defining a first surface and a second surfaceopposite the first surface, wherein the scaffold is substantiallyimpermeable to a hydrophobic active agent, and a silicone tubing havingwall permeable to the active agent, wherein a length of the siliconetubing is affixed to the first surface of the scaffold, wherein the twoends of the silicone tubing extend from the first surface, and wherein apath outlined by a second length of the tubing within the first lengthis circuitous.

The silicone tubing of the present implant is permeable to a hydrophobicactive agent, e.g., an anti-estrogen or a steroid, and serves as a depotof the hydrophobic active agent when the implant is implanted in asubject. The silicone tubing can be shaped such that the path outlinedby the tubing forms a circuitous pattern, e.g., on the surface of ascaffold, as described further below. Once implanted, a hydrophobicactive agent that is loaded in the silicone tubing elutes from thesilicone tubing into the surrounding tissue. Thus, the implant of thepresent disclosure can provide sustained, long-term delivery of thehydrophobic active agent without the silicone tubing being connected toa chamber or reservoir at the target tissue to hold, e.g., a solutioncontaining the hydrophobic active agent. In addition, the use of asingle tubing as both the conduit for loading the implant with varioussolutions as well as the depot for the active agent, solution exchangeis facilitated as the tubing provides a circular flow of solution,entering the implant from one end of the tubing and exiting from theother end.

An implant of the present disclosure provides for localized delivery ofthe hydrophobic active agent from the silicone tubing for treatment ofthe target tissue, while reducing the spread of the hydrophobic activeagent to non-target tissue and hence reducing systemic side effectsand/or toxicity. This can be achieved by attaching the silicone tubingto a scaffold, e.g., a backing, which serves as a barrier for diffusionof the hydrophobic active agent. Thus, the present implant can provideunidirectional, localized and sustained release of the hydrophobicactive agent at the site of implantation.

Implants for Delivering an Active Agent

An embodiment of the implant for delivering an active agent to a targettissue is shown in FIGS. 1A-C. The implant 1 includes a length ofsilicone tubing 2 affixed to a surface of a scaffold 4. The tubingcontains a central switchback 21 such that a first length of the tubing22 lies alongside a second length of the tubing 23. The first and secondlengths of the tubing together form a spiral pattern originating fromthe location of the central switchback. A regular spiral pattern allowsfor the tubing to be distributed at regular intervals over the surfaceof the scaffold between the location of the central switchback and thelength of tubing at the outer most edge of the spiral pattern. The firstlength of the tubing defines a first end 24 distal to the second length,and the second length of the tubing defines a second end 25 distal tothe first length. The first and second ends of the tubing extend outfrom the implant. The tubing serves as a depot for holding an activeagent, e.g., a drug, in the implant, from which the drug elutes into thesurrounding tissue.

The silicone tubing may be Silastic® Rx 50 tubing, as seen in FIG. 1C.This tubing is a biomedical grade silicone polymer approved by the U.S.Food and Drug Administration (FDA) as a medical device safe forimplantation in the human body. The tubing has an inner diameter of 0.76mm, and an outer diameter of 1.65 mm.

The scaffold 4 can be a substantially circular shape and can be sized tothe desired diameter to cover the target tissue. The scaffold can extendbeyond the spiral pattern formed by the silicone tubing. The scaffold 4is made of any suitable material that is substantially impermeable tothe active agent being eluted from the silicone tubing 2, to preventdiffusion of the active agent in the direction of the scaffold from thetubing, and achieve unidirectional delivery of the active agent from theimplant (see also, FIG. 12).

For a given length of the tubing on the surface of the scaffold, thelength of tubing may define a first side external to the outer wall ofthe tubing within a plane parallel to the surface of the scaffold, and asecond side external to the outer wall of the tubing opposite the firstside. For the silicone tubing having a central switchback and a spiralpattern of a first and second lengths of the tubing, as described above,the distance between the first and second lengths, as well as the rateat which the first and second lengths of the tubing move away from thelocation of the central switchback may define the distance between aportion of the first length of tubing and a portion of the second lengthof tubing on a first side of the portion of the first length of tubingand the distance between the portion of the first length of tubing and aportion of the second length of tubing on a second side of the portionof the first length of tubing, opposite the first side. For example, inFIGS. 2A-B, the distance between the first 22 and second 23 lengths ofthe silicone tubing 2 and the rate at which the first and second lengthsof the tubing move away from the location of the central switchback 21are such that a portion of the first length of tubing and a portion ofthe second length of tubing on the first side of the portion of thefirst length of tubing are in contact with each other substantiallyalong the spiral pattern, and the portion of the first length of tubingand a portion of the second length of tubing on the second side of theportion of the first length of tubing, opposite the first side, are incontact with each other substantially along the spiral pattern. Byadjusting the distance between the first and second lengths of thetubing and the rate at which the first and second lengths of the tubingmove away from the location of the central switchback, the total lengthof the silicone tubing 2 affixed to the scaffold 4 in a spiral patternmay be altered, to control the size of the target area to be treated andthe amount of drug held in the depot of the implant 1, and contribute toachieving the desired profile of drug release. The distribution of thesilicone tubing on the scaffold may also be adjusted to improveflexibility of the implant and facilitate furling or folding of theimplant during surgical operations, as described herein.

The present implant can be an imageable implant, which can be imaged byany suitable imaging method after implantation. Thus, the implant cancontain material that can be imaged using any suitable method, e.g.,mammography, ultrasonography, magnetic resonance imaging (MRI), etc. Theimageable material may be contained in any suitable component of theimplant, e.g., in the silicone tubing, the scaffold, and/or the fillport, described further below. The imageable material may be anysuitable material for use in imaging. In some embodiments, the imageablematerial includes metals, including non-magnetic metals, ceramic, or aradiopaque material. Radiopaque materials may include stainless steel,platinum, gold, iridium, tantalum, tungsten, silver, rhodium, nickel,bismuth or other radiopaque metals, mixtures of radiopaque metals,oxides of radiopaque metals, barium salts, iodine salts, iodinatedmaterials, and combinations thereof. In some cases, the imageablematerial is a contrast agent, e.g., gadolinium, iron, platinum,manganese, and compounds thereof.

With reference to FIGS. 3, 4, 5 and 6 which illustrate alternativeembodiments of the present implant, the silicone tubing 2 includes aplurality of switchbacks 21, a first switchback 21′ proximal to a firstend 24 of the tubing defining a first length of the tubing 22 betweenthe first end and the first switchback, a second switch back 21″ distalto the first switchback and proximal to a second end 25 of the tubingdefining a second length of the tubing 23 between the second end and thesecond switchback, and pairs of consecutive switchbacks, including thefirst and second switchbacks, defining a number of internal lengths ofthe tubing 26, where the first, second and internal lengths of thetubing lie along each other so as to form, e.g., a cascading rows ofarced (FIGS. 3 and 5) or parallel (FIGS. 4 and 6) lengths of the tubing.The distance between the outer walls of adjacent first, second andinternal lengths of the tubing may vary, depending on the desired drugelution profile and handling properties of the implant, as discussedabove. In some cases, the outer walls of adjacent first, second andinternal lengths of tubing contact each other substantially along thelengths of the tubing. In some cases, there may be gaps between theouter walls of adjacent first, second and internal lengths of thetubing.

The surface onto which the silicone tubing is affixed defines a shape,which may be any suitable shape for attaching the silicone tubing, andmay be adjusted based on the target tissue to be treated by the activeagent and/or the physical dimensions of the implantation site. The shapeof the scaffold in some cases is substantially circular (FIGS. 1A, 2A,3, 5, 6), or is rectangular (FIG. 4).

FIGS. 7 and 8 illustrate another embodiment of the present implant fordrug delivery. The implant may include a silicone tubing 2, whichcontains a switchback in the form of a terminal loop 27 that defines afirst length of the tubing 22 and a second length of the tubing 23. Thesecond length of tubing may be substantially straight and define acentral axis around which the first length of tubing forms a helicalstructure by winding around and along the central axis. The pitch, ordistance between the outer wall of adjacent portions of the first lengthof the tubing at consecutive complete turns of the helix, may beadjusted as desired, and may be such that there is a gap between theportions (FIG. 7) or such that the outer walls of adjacent portions ofthe first length of the tubing at consecutive complete turns of thehelix may be in contact with each other (FIG. 8). Thus, the pitch of thehelix may be adjusted to control the amount of drug contained in theimplant 1, and contribute to achieving the desired profile of drugrelease.

FIG. 9 shows an embodiment of the present implant for drug delivery 1where the silicone tubing 2 includes a single switch back 21 located atthe distal end. The switch back defines a first length of the tubing 22and a second length of the tubing 23, where the first and second lengthsof the tubing are intertwined with each other in double-helix form. Thepitch of the helices and the total length of the tubing from the end ofthe first and second lengths to the switchback can be adjusted to fitthe target tissue dimensions and to control the amount of drug held inthe depot of the implant 1, to achieve the desired profile of drugrelease.

With reference to FIGS. 10A-B, there is shown the design for a remotefill port 8, which may be connected to the silicone tubing 2 to form arefillable, closed system. The remote fill port contains a soliddetectable backing 9, which allows for, e.g., percutaneous locating ofthe port with a magnet finder if the backing is magnetic. There are twoseparate chambers in the port 10, 11, each feeding into a first end 24and second end 25 of the silicone tubing, e.g., Silastic® siliconetubing, respectively. The port also contains suture tabs 14 at its baseto allow for suturing to the soft tissue upon implantation, thus helpingto resist turning or movement of the port.

FIGS. 11A-C illustrates a manner in which the silicone tubing 2 of thepresent implant may be filled with a displacing solution 204 bydisplacement of an initial content 202, e.g., for loading the tubingwith a drug. The initial content may be a gas, e.g., air, or an initialsolution, e.g., an organic solvent, and the displacing solution may be adrug solution. The silicone tubing is connected to a remote fill port,as described in FIGS. 10A-B, and the displacing solution is introducedinto the tubing (FIG. 11A) through a first end of the tubing 24 byintroducing the solution into a first remote fill port chamber connectedto the first end of the tubing. The solution is moved through the tubingby any suitable method, including gravity flow, positive back pressureapplied proximally to the first end of the tubing 24, and/or negativevacuum pressure applied proximally to the second end of the tubing 25.As the solution migrates into the silicone tubing of the implant (FIG.11B), the initial content of the silicone tubing is displaced, pushedthrough the second end of the tubing and removed via a second remotefill port chamber. Eventually, the initial content of the tubing isdisplaced completely (FIG. 11C), without introducing any air pockets orother inhomogeneities through the tubing.

In certain cases, e.g., where the liquid flow through the siliconetubing is non-turbulent, the first and second ends are connected withinthe implant such that an amount of liquid introduced into the implantfrom the first end under sustained pressure will exit the implant fromthe second end when a volume of liquid in the implant approximatelyequal to the internal volume of the silicone tubing between the firstand second ends is displaced by the applied pressure.

As illustrated in FIG. 12, the implant 1, having a silicone tubing 2affixed to a scaffold 4, when loaded with a drug, as described in FIGS.11A-C, can provide localized, unidirectional delivery of the drug in atissue in which the implant is placed. The implant is positioned suchthat the drug in the implant diffuses preferentially to a target tissue32, while the scaffold prevents diffusion of the drug to a non-targettissue 34.

With reference to FIG. 13A, there is shown an implant 1, having ascaffold 4, e.g., a breast implant, implanted in the breast 42. Theimplant is placed superficial to the pectoralis muscle 44. The siliconetubing 2, e.g., Silastic® tubing, functioning as the drug elutingdelivery system, is seen on the anterior surface of the scaffold 4, indirect contact with the overlying breast tissue. A drug, e.g., anantiestrogen drug, elutes from a drug-containing solution in the tubinginto the breast tissue 42, but the breast implant hinders diffusion ofthe drug to the pectoralis muscle 44 and prevents systemic circulationof the drug.

With reference to FIG. 13B, there is shown an implant 1 with a siliconetubing 2, e.g., Silastic® silicone tubing, affixed thereto, in anteriorbirds-eye view. The continuation of the tubing in each direction isdirected to the remote fill port 8. The remote fill port may beimplanted subcutaneously where it provides ready access to the contentsof the silicone tubing in the implant for introducing and/or removingsolutions. The remote fill can be implanted at any convenient location,such as in the axilla (as shown in FIG. 13B) or at the breast fold.

The present implant has sufficient flexibility so as to allow a medicalpractitioner, e.g., a surgeon, to furl or roll the implant into a morecompact structure and facilitate placement of the implant duringsurgery. FIGS. 14A-D illustrate various ways in which the presentimplant may be furled for implantation. Starting from the initial planarconfiguration (FIG. 14A), in one case, two opposite ends of the scaffold4 is rolled over on the side of the silicone tubing 2 to form aconfiguration suitable for delivery to a site of implantation (FIG.14B). In addition to furling the ends, the center of the scaffold can befolded to further reduce the width of the cross-sectional profile of theimplant to form a configuration suitable for delivery (FIG. 14C). Inaddition, the entire scaffold is rolled over from one end to another onthe side of the silicone tubing to form a configuration suitable fordelivery (FIG. 14D). Once the implant is placed in the tissue ofinterest, the implant is unfurled into its functional configuration,which can be similar to the initial planar configuration (FIG. 14A). Theimplant may be secured in place by any suitable means, such as one ormore suture tabs affixed to the implant.

FIG. 15 illustrates the placement of an embodiment of the presentimplant 1 in the prostate gland 52, in sagittal view. The siliconetubing 2 has an intertwined, double-helical form, as described in FIG.9, and is sized to fit the prostate gland. A dual fill port 8 isattached to the ends of the silicone tubing and implanted under the skinto allow filling and removing of drugs as desired.

Silicone Tubing

The silicone tubing can be any biocompatible tubing that is permeable toa hydrophobic active agent of interest and allows for diffusion of theactive agent through the wall of the tubing. The silicone tubing can bea biomedical grade, platinum-cured, elastomeric silicone tubing.Suitable silicone tubing includes SILASTIC silicone tubing availablefrom Dow Corning Co. In some instances, the silicone tubing isSILASTIC-Rx50, having a shore value of around 50. Other exemplarysilicone tubing is described in e.g., U.S. Pat. Nos. 3,279,996 and4,012,497, which are incorporated by reference herein.

Without wishing to be held to theory, the Silastic® polymer may allowfor the diffusion of various steroids under Fick's law of diffusion.Rate of steroid diffusion from the tube is primarily limited bysolubility of the solute in the polymer matrix, rather than by the fluidboundary layer and will be geared by the solubility and amount of theactive agent, e.g., a chemopreventive agent.

The silicone tubing can have any physical and material properties (e.g.,inner diameter, wall thickness, flexibility, tensile strength, etc.)suitable for use in the present implant. The physical and materialproperties can in some cases be substantially uniform along the lengthof the tubing that is attached to the scaffold and/or is in directcontact with the target tissue so as to provide controlled delivery ofthe active agent.

The silicone tubing can have any dimensions suitable for delivering theactive agent to a target tissue over the desired duration. The innerdiameter of the silicone tubing may be 0.1 mm or more, e.g., 0.3 mm ormore, 0.5 mm or more, including 0.6 mm or more, and may be 5.0 mm orless, e.g., 3.0 mm or less, 1.0 mm or less, including 0.9 mm or less. Insome cases, the inner diameter of the silicone tubing is in the range of0.1 to 5.0 mm, e.g., 0.1 to 3.0 mm, 0.3 to 1.0 mm, including 0.5 to 0.9mm. The outer diameter of the silicone tubing may be 0.5 mm or more,e.g., 0.8 mm or more, 1.0 mm or more, including 1.2 mm or more, and maybe 10 mm or less, e.g., 5.0 mm or less, 3.0 mm or less, including 2.0 mmor less. In some cases, the inner diameter of the silicone tubing is inthe range of 0.5 to 10 mm, e.g., 0.8 to 5.0 mm, 1.0 to 3.0 mm, including1.2 to 2.0 mm. The wall thickness of the silicone tubing may be 0.1 mmor more, e.g., 0.2 mm or more, 0.3 mm or more, including 0.4 mm or more,and may be 3.0 mm or less, e.g., 1.0 mm or less, 0.8 mm or less,including 0.6 mm or less. In some cases, the wall thickness of thesilicone tubing is in the range of 0.1 to 3.0 mm, e.g., 0.1 to 1.0 mm,0.2 to 0.8 mm, including 0.3 to 0.6 mm.

The length of the silicone tubing may vary depending on the desiredamount of tubing (volume of the wall and/or the internal volume), thesize of the implant, target tissue and/or implantation site, the desiredprofile of drug release from the implant, etc.

The silicone tubing is shaped in the present implant to serve as a depotfor the active agent, a source of sustained release of the active agent,and to allow simple and efficient exchange of contents of the tubing.The silicone tubing can contain at least one switchback between thefirst and second ends of the tubing and the length of the tubing canoutline a circuitous path such that a longer total length of the tubingcan be contained in a space whose dimensions are smaller than the totallength of the tubing than if the tubing were straight or not circuitous.In some cases, the tubing forms a single switchback and the two lengthsof the tubing defined relative to the switchback are intertwined witheach other into a double helical form. In some cases, the tubing isattached to a scaffold and outlines a circuitous path on the surface ofthe scaffold, as described in further detail herein.

Scaffold

The scaffold can be any biocompatible solid but flexible scaffold thatis substantially impermeable to a hydrophobic active agent of interestand prevents diffusion of the active agent from one side of the scaffoldto the other. The scaffold may be made of a material, e.g., a polymericmaterial, that is substantially impermeable to the hydrophobic activeagent, and/or may have structural features (thickness, shape, etc.) thateffectively prevent the hydrophobic active agent from diffusing from oneside of the scaffold to the other. The scaffold can be a membrane, afilm or a flexible sheet. In some cases, the scaffold may be a breastimplant.

The scaffold can be non-degradable when implanted in a physiologicalenvironment. Thus, the scaffold may be sufficiently resistant todegradation by chemical, physical and/or enzymatic means when implantedat the target tissue, to retain its function as a scaffold and a barrierfor diffusion of the active agent for the duration of use of theimplant.

In some embodiments, the scaffold is made of a biocompatible polymericmaterial. Some relevant factors to be considered in choosing a polymericmaterial for the scaffold include: compatibility of the polymer with thebiological environment of the implant, compatibility of the active agentwith the polymer, ease of manufacture, a half-life in the physiologicalenvironment, etc. Depending on the relative importance of thesecharacteristics, the compositions can be varied. Several such polymersand their methods of preparation are well-known in the art. See, forexample, U.S. Pat. Nos. 4,304,765; 4,668,506; 4,959,217; 4,144,317, and5,824,074, Encyclopedia of Polymer Science and Technology, Vol. 3,published by Interscience Publishers, Inc., New York, latest edition,and Handbook of Common Polymers by Scott, J. R. and Roff, W. J.,published by CRC Press, Cleveland, Ohio, latest edition; which areincorporated herein by reference.

The polymers of interest may be homopolymers, copolymers, straight,branched-chain, or cross-linked derivatives. Suitable polymers include:polycarbamates or polyureas, cross-linked poly(vinyl acetate) and thelike, ethylene-vinyl ester copolymers having an ester content of 4 to80% such as ethylene-vinyl acetate (EVA) copolymer, ethylene-vinylhexanoate copolymer, ethylene-vinyl propionate copolymer, ethylene-vinylbutyrate copolymer, ethylene-vinyl pentantoate copolymer, ethylene-vinyltrimethyl acetate copolymer, ethylene-vinyl diethyl acetate copolymer,ethylene-vinyl 3-methyl butanoate copolymer, ethylene-vinyl 3-3-dimethylbutanoate copolymer, and ethylene-vinyl benzoate copolymer, or mixturesthereof.

Additional examples include polymers such as: poly(methylmethacrylate),poly(butylnethacrylate), plasticized poly(vinylchloride), plasticizedpoly(amides), plasticized nylon, plasticized soft nylon, plasticizedpoly(ethylene terephthalate), natural rubber, silicone, poly(isoprene),poly(isobutylene), poly(butadiene), poly(ethylene),poly(tetrafluoroethylene), poly(vinylidene chloride),poly(acrylonitrile, cross-linked poly(vinylpyrrolidone), chlorinatedpoly(ethylene), poly(trifluorochloroethylene), poly(ethylenechlorotrifluoroethylene), poly(tetrafluoroethylene), poly(ethylenetetrafluoroethylene), poly(4,4′-isopropylidene diphenylene carbonate),polyurethane, poly(perfluoroalkoxy), poly(vinylidenefluoride),vinylidene chloride-acrylonitrile copolymer, and vinyl chloride-diethylfumarate copolymer.

Some further examples of polymers include: poly(dimethylsiloxanes),ethylene-propylene rubber, silicone-carbonate copolymers, vinylidenechloride-vinyl chloride copolymer, vinyl chloride-acrylonitrilecopolymer, vinylidene chloride-acrylonitrile copolymer, poly(olefins),poly(vinyl-olefins), poly(styrene), poly(halo-olefins), poly(vinyls)such as polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linkedpolyvinyl butyrate, ethylene ethylacrylate copolymer, polyethylhexylacrylate, polyvinyl chloride, polyvinyl acetals, plasticizedethylene vinylacetate copolymer, polyvinyl alcohol, polyvinyl acetate,ethylene vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate,polyvinylformal, poly(acrylate), poly(methacrylate), poly(oxides),poly(esters), poly(amides), and poly(carbonates), or mixtures thereof.

The shape and dimensions of the scaffold may vary depending on the sizeof the target tissue and/or implantation site, the amount of tubingneeded to achieve a desired profile of drug release from the implant,etc. In some embodiments, the scaffold is substantially planar. Thescaffold may have any suitable thickness, and may have an averagethickness that is 0.01 mm or more, e.g., 0.1 mm or more, 0.5 mm or more,1 mm or more, 5 mm or more, 10 mm or more, including 20 mm or more, andmay have an average thickness that is 40 mm or less, e.g., 30 mm orless, 20 mm or less, 10 mm or less, 5 mm or less, 1 mm or less,including 0.5 mm or less. In some embodiments, the scaffold has athickness in the range of 0.01 to 30 mm, e.g., 0.1 to 20 mm, 0.1 to 10mm, 0.5 to 10 mm, including 1 to 5 mm. The scaffold may be circular,oval, rectangular, square, etc. In some cases, the scaffold issubstantially circular, having an average diameter of 0.1 cm or more,e.g., 1 cm or more, 2 cm or more, 5 cm or more, 8 cm or more, 10 cm ormore, including 30 cm or more, and has an average diameter of 100 cm orless, e.g., 50 cm or less, 20 cm or less, 10 cm or less, including 5 cmor less. In some embodiments, a substantially circular scaffold has anaverage diameter in the range of 0.1 cm to 100 cm, e.g., 1 cm to 50 cm,including 1 cm to 20 cm.

The scaffold can be flexible enough such that the implant can be foldedand/or rolled into a configuration suitable for delivery into the siteof implantation through, e.g., a surgically made incision.

In embodiments of the present disclosure where the silicone tubing isaffixed to a first surface that is opposite to a second surface of ascaffold, the silicone tubing can outline a circuitous path along thefirst surface. The circuitous path may be any suitable pattern,including a spiral, cascading lengths of tubing, etc.

The distance between portions of the tubing that lie next to each otherin the circuitous pattern may vary. In some cases, the smallest distancebetween the outer walls of adjacent lengths of the tubing at a positionalong the circuitous path is, 0 fold or more, e.g., 0.1 fold or more,0.2 fold or more, 0.3 fold or more, 0.5 fold or more, 0.75 fold or more,including 1.0 fold or more of the outer diameter of the tubing, and is2.0 fold or less, e.g., 1.5 fold or less, 1.0 fold or less, 0.8 fold orless, 0.6 fold or less, 0.5 fold or less, 0.4 fold or less, including0.3 fold or less of the outer diameter of the tubing. In some instances,the smallest distance between the outer walls of adjacent lengths of thetubing at a position along the circuitous path is in the range of 0 to2.0 fold, e.g., 0 to 1.0 fold, 0 to 0.8 fold 0.1 to 0.6 fold, including0.1 to 0.4 of the outer diameter of the tubing.

In some embodiments, by outlining a circuitous path, the silicone tubingcovers a large fraction of the area of the first surface of thescaffold. In some cases, the silicone tubing covers 10% or more, e.g.,20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% ormore, including 80% or more, and covers 100% or less, e.g., 90% or less,80% or less, 70% or less, 60% or less, including 50% or less of thefirst surface of the scaffold. In some cases, the silicone tubing covers10% to 100%, e.g., 20% to 90%, 30% to 80%, including 40% to 70% of thearea of the first surface of the scaffold.

The silicone tubing may be attached to the surface of the scaffold usingany convenient method. In some embodiments, the silicone tubing may beattached to the surface of the scaffold with a biocompatible adhesivedisposed between the surface and the tubing, or by using a fixationdevice such as a suture to stitch or sew the tubing onto the scaffold,etc.

The implant can include any suitable element for securing the implant totissue at the site of implantation. In some cases, the implant includesone or more suture tabs. Any suitable suture tab may be used. In someembodiments, the scaffold includes one or more suture tabs that may beused to secure the implant at the site of implantation. In some cases,one or more suture tabs may be affixed to the silicone tubing fir use insecuring the implant at the site of implantation.

Active Agents

The active agents that find use in the present implant for delivery arehydrophobic/lipophilic active agents. The hydrophobicity orlipophilicity of the hydrophobic compound, as defined by thedistribution coefficient (log D) between water and octanol, may be 4 orhigher, e.g., 4.5 or higher, 5 or higher, and may be 10 or less, e.g.,9.5 or less, including 9 or less. Thus, the hydrophobicity of thehydrophobic compound, as defined by log D between water and octanol, maybe in the range of 4 to 10, or 4.5 to 9.

The active agent may be any suitable active agent for local delivery toa site of implantation by the present implant. In some instances, theactive agent is an anti-cancer drug or a cancer chemopreventive drug,for, e.g., breast cancer, prostate cancer, etc.

In some embodiments, the hydrophobic active agent is a steroid. In someembodiments, a steroid active agent is an estrogen, including estradiol,or other agonists of the estradiol receptor. The steroid active agentmay include 17 beta estradiol, 17 alpha estradiol and their hydroxylatedmetabolites with or without subsequent glucuronidation, sulfation,esterification or O-methylation; an estradiol precursor; an activeestradiol metabolite such as estrone and estriol; an active analog suchas mycoestrogens and phytoestrogens including coumestans, prenylatedflavonoid, isoflavones (e.g. genistein, daidzein, biochanin A,formononetin and coumestrol).

In some embodiments, a steroid active agent is a modulator capable ofpositively influencing the activity of the estradiol receptor(s) or ofenhancing the binding and/or the activity of estradiol towards itsreceptor such as a selective estrogen receptor modulator (SERM)including tamoxifen and a derivative thereof including4-hydroxytamoxifen, clomifene, raloxifene, toremifene, bazedoxifene,lasofoxifene, ormeloxifenem, tibolone and idoxifene; a selectiveestrogen receptor down-regulator (SERD) including fulvestrant,ethamoxytriphetol and nafoxidine; and a high dose estradiol such asdiethylstilbestrol and ethinyloestradiol; and testosterone. The log Dfor fulvestrant is around 8.47, tamoxifen is around 6.122 and raloxifeneis around 5.406.

In some embodiments, a steroid active agent is a progestogen, such asprogesterone or progesterone analogues. Other suitable progestogens mayinclude, for example, allyloestrenol, dydrogesterone, lynestrenol,norgestrel, norethyndrel, norethisterone, norethisterone acetate,gestodene, levonorgestrel, medroxyprogesterone, and megestrol acetate.

In some embodiments, a steroid active agent is a modulator or inhibitorof the progesterone receptor. Suitable steroid active agent may includemifepristone (RU-486 or analogs thereof such as11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(e-methyl-1-butynyl)-4,9-estradien-3-oneand11β-(4-acetophenyl)-17β-hydroxy-17α-(3-methyl-1-butynyl)-4,9-estradien-3-one.

In some embodiments, a steroid active agent is a testosterone, orprecursors or derivatives thereof, such as 17 β-alkanoyl esters oftestosterone, including C₁₋₁₅ saturated or unsaturated straight orbranched chain alkanoyl esters, such as testosterone-17-acetate andtestosterone-17-propionate, methyltestosterone, androstenedione,adrenosterone, dehydroepiandrosterone, oxymetholone, fluoxymesterone,methandrostenolone, testolactone, pregnenolone,17α-methylnortestosterone, norethandrolone, dihydrotestosterone,danazol, oxymetholone, androsterone, nandrolone, stanozolol,ethylestrenol, oxandrolone, bolasterone and mesterolone, testosteronepropionate, testosterone cypionate, testosterone phenylacetate, andtestosterone enanthate, testosterone acetate, testosterone buciclate,testosterone heptanoate, testosterone decanoate, testosterone caprate,testosterone isocaprate, isomers and derivatives thereof, and acombination thereof.

In some embodiments, a steroid active agent is a corticosteroid.Examples of corticosteroids include fluocinolone, triamcinolone,cortisone, prednisolone, flurometholone, dexamethasone, medrysone,loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone,prednisone, methylprednisolone, riamcinolone hexacatonide, paramethasoneacetate, diflorasone, fluocinonide, derivatives thereof, and mixturesthereof.

In some embodiments, the lipid active agent is cholesterol, orderivatives thereof. Cholesterol derivatives may include7β-hydroxycholesterol 7-ketocholesterol, 7-ketocholesteryl acetate,25-hydroxycholesterol, 24,25-epoxycholesterol, diacetylenic cholesterol,cholest-4-ene-3,6-dione, cholest-4-en-3-one, cholesteryl behenate,cholesteryl benzoate, cholesteryl butyrate, cholesteryl caprate,cholesteryl caproate, cholesteryl caprylate,cholesteryl-3,5-dinitrobenzoate, cholesteryl formate,cholesteryl-β-D-glucoside, cholesteryl hemisuccinate, cholesterylheptylate, cholesteryl heptadecanoate, cholesteryl hydrogen phthalate,cholesteryl isobutyrate, cholesteryl isovalerate, cholesteryl laurate,cholesteryl linoleate, cholesteryl methyl succinates, cholesterylmyristate, cholesteryl nervonate, cholesteryl-p-nitrobenzoate,cholesteryl oleate, cholesteryl oleyl carbonate, cholesteryl palmitate,cholesteryl palmitelaidate, cholesteryl palmitoleate, cholesterylphosphoryl choline, cholesteryl polyethylene glycols, cholesterylpropionate, cholesteryl N-propyl carbonate, cholesteryl1-pyreecarbonate, cholesteryl (pyren-1-yl) hexanoate, cholesterylstearate, cholesteryl-P-tosylate, cholesteryl valerate, thiocholesterol,and cholesteryl sulfate.

Cholesterol derivatives may further include lanosterol,14-nor-lanosterol, 14-nor,24,25-dihydrolanosterol, Δ7-cholestenol,4α-methyl-Δ7-cholestenol, 4α-methyl-Δ8-cholestenol, dehydrocholesterol,cholestenone, cholestanone, cholestanol, coprosterol (coprostanol),coprostanone, Ia-hydroxycholesterol, 7α-hydroxy-4-cholesten-3 one,5β-cholestan-3α,7α,12α,26-tetrol, 7α,12α-dihydroxy-4-cholesten-3-one,5β-cholestan-3α,7α,12α-triol, 5β-cholestan-3α,7α-diol,5β-cholestan-3α,7α,26-triol, 5-cholestene-3β,7β-diol,5-cholestene-3β,20α-diol, 5-cholestene-3β,22(R)-diol,5-cholestene-3β,22(S)-diol, 5-cholestene-3β,25-diol,5α-choles-7-en-3β-ol, 5α-choles-3β-ol-7one, 5α-cholestan-3β-ol,5β-cholestan-3α-ol, α1-sitosterol, β-sitosterol, γ-sitosterol,stigmasterol, stigmastanol, fucosterol, campesterol, ergostanol,α-ergostenol, β-ergostenol, γ-ergostenol, dinosterol, ergosterol,cholestane, cholestene, coprostane, ergostane, lanostane, andcampestane.

Cholesterol derivatives may further include cholesterol acetate,cholesterol arachidonate, cholesterol behenate, cholesterol butyrate,cholesterol docosanoate, cholesterol dodecanoate, cholesteroleicosapentanoate, cholesterol elaidate, cholesterol erucate, cholesterolheptadecanoate, cholesterol heptanoate, cholesterol hexanoate,cholesterol linoleate, cholesterol α-linolenate, cholesterolγ-linolenate, cholesterol nonanoate, cholesterol octanoate, cholesterololeate, cholesterol palmitate, cholesterol palmitoleate, cholesterolpentanoate, cholesterol propanoate, cholesterol tetracosanoate,cholesterol tetracosenoate, cholesterol methyl ether, cholesterol ethylether, cholesterol n-propyl ether, cholesterol 2-propyl ether,cholesterol 1-n-butyl ether, cholesterol 2-n-butyl ether, cholesterolisobutyl ether, and cholesterol tert-butyl ether.

In some embodiments, the hydrophobic active agent is an inhibitor ofmediators of cellular signaling pathways, such as an inhibitor of polyadenosine diphosphate (ADP) ribose polymerase (PARP), mammalian targetof rapamycin (m-TOR), Raf kinase and epidermal growth factor receptor(EGFR). In some embodiments, the hydrophobic active agent is a modifierof DNA methylation, such as a histone deacetylase inhibitor or ademethylation agent. In some embodiments, the hydrophobic active agentis an immunomodifier, such as an inhibitor of cytotoxicT-lymphocyte-associated protein 4 (CTL-4), programmed cell death protein1 (PD-1), and anaplastic lymphoma kinase (ALK).

The hydrophobic active agent may be formulated in any suitable mannerfor loading the silicone tubing of the present implant, before or afterimplantation of the implant in a target tissue of a subject. Thehydrophobic active agent may be solubilized in any suitable solvent,e.g., an organic solvent. The organic solvent may include ethanol,methanol, benzyl alcohol, benzyl benzoate, dimethylsulfoxide (DMSO),dimethylformamide (DMF), castor oil, etc., and combinations thereof.Other organic solvents include glycofurol, propylene glycol,polyethylene glycol 400, Lutrol® and dihydrolipoic acid.

In some embodiments, the hydrophobic active agent is present in thesilicone tubing of the present implant. The hydrophobic active agent maybe present within the wall of the silicone tubing, on the surface of theinner wall of the silicone tubing, and/or present in the internal volumeof the silicone tubing in liquid form, e.g., dissolved in a solution inthe tubing. In some embodiments, the active agent is present in thetubing at a concentration, per cm of tubing, of 0.0001 mg or more, e.g.,0.001 mg or more, 0.005 mg or more, 0.01 mg or more, 0.05 mg or more,0.1 mg or more, including 1 mg or more, and is present in the tubing ata concentration, per cm of tubing, of 10 mg or less, e.g., 5 mg or less,1 mg or less, 0.1 mg or less, 0.5 mg or less, including 0.1 mg or less.In some embodiments, the active agent is present in the tubing at aconcentration, per cm of tubing, in the range of 0.0001 to 10 mg, e.g.,0.001 to 1 mg, including 0.01 to 0.1 mg.

Fill Port

In some embodiments, the present implant includes a fill port configuredto provide access to the internal volume of the silicone tubing, beforeand after implantation. The fill port can include one or morechambers/lumens, where each lumen can be connected to an end of thesilicone tubing that extends out from the portion of the implant thatresides or is intended to reside at the target tissue. Thus, each of thetwo ends of the silicone tubing of the present implant may be connectedto a chamber of a fill port. Any suitable solution may be introducedinto the silicone tubing of the implant by applying the solution to onefill port, allowing the solution to displace the contents of the tubing,and removing the displaced contents through the second fill port. Insome embodiments, the fill port is a dual lumen fill port having twochambers, each chamber being in fluid communication at the fill portwith one end of the silicone tubing. The fill port may be implantedsubcutaneously at any convenient site on the subject.

The fill port may have other features that can facilitate the use of theimplant. In some embodiments, the fill port includes a detectablebacking. In some cases, the fill port includes a magnetic backing tofacilitate locating of the fill port using a magnet finder. In somecases, the detectable backing is an imageable backing, e.g., a backingthat is compatible with an imaging system, such as mammography,ultrasonography, magnetic resonance imaging (MRI), etc. In someinstances, the fill port includes suture tabs at its base for suturingthe fill port to the tissue after implantation.

Methods

Method of Delivering a Hydrophobic Active Agent

Also provided herein is a method of locally delivering a hydrophobicactive agent to a target tissue in a subject, by placing an implant ofthe present disclosure in a target tissue. The implant is positioned inthe target tissue such that the active agent is released from thesilicone tubing and delivered to the target tissue in a sustained mannerover a time period. Where the implant includes a scaffold to which thesilicone tubing is attached, the implant can be oriented such that thescaffold serves to prevent or reduce diffusion of the active agent intonon-target tissue, such as muscle and other highly-vascularized tissue,to reduce off-target side effects and/or systemic side effects. Thus theimplant of the present disclosure can achieve localized delivery of theactive agent to target tissue.

In some embodiments, implanting includes folding or furling the implantinto a configuration suitable for delivery of the implant into theimplantation site. Such a delivery configuration will depend on thematerial properties the silicone tubing, and if present, the scaffold,and on the shape of the silicone tubing and/or scaffold. Thus, in somecases, two opposite edges of a scaffold may be furled towards themiddle, wrapping the silicone tubing inside the fold, to reduce thewidth of the implant. In some embodiments, the middle of the implant mayfurther be folded to form a ridge to further reduce the width of theimplant. In other instances, the scaffold may be rolled from one end tothe other, wrapping the silicone tubing inside the fold, to reduce thewidth of the implant. Any other suitable method may be used to reducethe length of the longest dimension of the scaffold and facilitateinsertion of the implant into the site of implantation.

Once the implant is placed at the implantation site in its deliveryconfiguration, the scaffold may be unfurled into its functionalconfiguration. The functional configuration is one that provides for thelocalized, unidirectional delivery of the active agent to the targettissue, as described herein. The implant in its functional configurationmay also be secured at the implantation site using any suitable means,including suturing to the target tissue.

The implant may or may not be loaded with the active agent before theimplanting procedure.

The target tissue may be any suitable target tissue for implanting thepresent implant for delivering a hydrophobic active agent. In someembodiments, the target tissue is breast tissue. In some cases, animplant with a scaffold may be surgically placed over the pectoralismuscle and under the breast tissue, with the surface of the scaffold towhich the silicone tubing is attached facing the ventral (or anterior)direction, toward the breast tissue, and the opposite surface of thescaffold facing the dorsal (or posterior) direction, toward thepectoralis muscle. In some embodiments, the target tissue is prostatetissue. In some cases, the implant without a scaffold may be positionedin the prostate through a rectal incision. In some embodiments, thetarget tissue is uterine, brain, skin, ovarian, gastrointestinal,bladder, muscle, liver, kidney or pancreatic tissue.

A non-target tissue to which the active agent is not delivered ordelivered at a reduced level compared to the target tissue by thepresent implant may include blood (e.g., whole blood, blood serum,etc.), and may also include other tissues depending on the targettissue. In some cases, where the target tissue is breast tissue, thenon-target tissue may include the pectoral muscle.

The subject may be any suitable subject, e.g., human subject, who may bein need of treatment by administration of the hydrophobic active agent.In some cases, the subject is a subject diagnosed with a disease, e.g.,a cancer, such as breast cancer or prostate cancer. In some cases, thesubject is a subject at risk of developing a disease, e.g., cancer, suchas breast cancer. In such cases, the active agent may be an anti-cancerdrug that can reduce the tumor burden, slow the progression of thecancer, retard or prevent tumorigenesis and/or retard or prevent therecurrence of a tumor in the subject.

The present implant provides for release of an amount of the activeagent into the surrounding environment, e.g., surrounding tissue, whenloaded with the active agent. In some cases, the implant releases theactive agent at an average rate of 1 ng per cm of tubing per day ormore, e.g., 3 ng per cm of tubing per day or more, 5 ng per cm of tubingper day or more, 7 ng per cm of tubing per day or more including 10 ngper cm of tubing per day or more, and releases the active agent at anaverage rate of 50 ng per cm of tubing per day or less, 40 ng per cm oftubing per day or less, 30 ng per cm of tubing per day or less, 20 ngper cm of tubing per day or less, including 10 ng per cm of tubing perday or less. In some cases, the implant releases the active agent at anaverage rate of 1 to 50 ng per cm of tubing per day, e.g., 1 to 30 ngper cm of tubing per day, 2 to 20 ng per cm of tubing per day including3 to 10 ng per cm of tubing per day.

In some embodiments, the implant achieves an average level of the activeagent in the target tissue of 50 nM or more, e.g., 75 nM or more, 100 nMor more, 125 nM or more, including 150 nM or more, and achieves anaverage level of the active agent in the target tissue of 1,000 nM orless, e.g., 800 nM or less, 600 nM or less, 400 nM or less, including300 nM or less. In some embodiments, the implant achieves an averagelevel of the active agent in the target tissue in the range of 50 to1,000 nM, e.g., 75 to 600 nM, 100 to 400 nM, including 100 to 300 nM.

The implant can deliver the active agent in an amount effective tofunctionally alter cellular function and/or biochemical signalingpathways in the target tissue. The cellular function and biochemicalsignaling pathways may include expression level (protein or mRNA) of areceptor targeted directly or indirectly by the active agent, and/orproliferation of tumor cells.

In some embodiments, the implant delivers a therapeutically effectiveamount of the active agent to the target tissue.

The active agent delivered specifically to a target tissue using thepresent implant may be present in a non-target tissue at significantlylower level than in the target tissue. In some embodiments, the activeagent delivered specifically to a target tissue is present in non-targettissue, such as in blood, at a lower percentage compared to the targettissue by 50% or more, e.g., 75% or more, 80% or more, 85% or more, 90%or more, 95% or more, 98% or more, 99% or more, up to about 100%, and ispresent at a lower percentage by 100% or less, 99% or less, 98% or less,97% or less, 95% or less, 90% or less, 85% or less, including 80% orless. In some embodiments, the active agent delivered specifically to atarget tissue is present in non-target tissue, such as in blood, at alower percentage compared to the target tissue in the range of 50 to100%, e.g., 75 to 100%, 85 to 100%, 90 to 100%, including 95 to 100%.

In some embodiments, the active agent delivered specifically to a targettissue may be present in non-target tissue, such as in blood, at anaverage level of 10 nM or less, e.g., 8 nM or less, 5 nM or less,including 4 nM or less. In some embodiments, the active agent deliveredspecifically to a target tissue may be substantially undetectable in thenon-target tissue, such as in blood.

The implant of the present disclosure can provide sustained release ofthe active agent into the target tissue with a single loaded dose of theactive agent. In some cases, the active agent is released for 5 days ormore, e.g., 1 week or more, 5 weeks or more, 10 weeks or more, 20 weeksor more, 50 weeks or more, 2 years or more, 5 years or more, including10 years or more, and is released for 60 years or less, e.g., 50 yearsor less, 40 years or less, 10 years or less, 1 year or less, including26 weeks or less, into the target tissue with a single loaded dose ofthe active agent. In some embodiments, the active agent is released intothe target tissue with a single loaded dose of the active agent for atime period in the range of 5 days to 60 years, e.g., 1 week to 50years, 5 weeks to 40 years, 10 weeks to 10 years, including 20 weeks to1 year.

Method of Loading and Reloading the Implant

The present implant including a silicone tubing depot for a hydrophobicactive agent can be loaded and reloaded, before or after implantation.This allows for control of the dosage, type of drug or removal of anactive agent from the implant in a simple manner. In some cases, thetubing may be connected at the ends to a fill port, as described above.The tubing can be filled by applying a solution to one end of thetubing, e.g., via a chamber on the fill port, letting the solution flowthrough the tubing towards the opposite end of the tubing. The solutionmay advance through the tubing by gravitational flow, or a pressure maybe applied to the tubing. The pressure may be a positive pressurepushing the solution from the end to which the solution is initiallyapplied, or may be a negative pressure applied to the opposite end ofthe tubing to draw the solution into the tubing.

Where the tubing is substantially uniform in inner diameter throughoutthe implant, a steady, gradual flow of the solution allows for thesolution to fill the tubing without introducing air bubbles or localinhomogeneities.

Using such a method, the tubing may be filled with a solution containingan active agent. Removal of the solvent subsequent to filling, e.g., byevaporation, can result in the active agent being deposited on the innersurface of the wall of the tubing, thereby loading the tubing with theactive agent. The solution may also be left in the tubing and the tubingmay be sealed at both ends, thereby loading the tubing with the activeagent. An active agent loaded in the tubing may be removed from thetubing by filling the tubing with a solution into which the active agentcan diffuse out of the wall of the tubing. It is also possible to changethe concentration of active agent in the tubing, switch the type ofactive agent present in the tubing, etc.

The implant, including the silicone tubing and/or fill port, and theactive agent may be imaged when implanted, e.g., by mammography,ultrasonography, magnetic resonance imaging (MRI), etc. Thus, theimageable nature of the implant and the active agent may facilitaterefilling and/or removal of solution from the implant.

In some embodiments, the tubing may be loaded with an active agentduring the manufacture of the tubing, such as through room temperaturevulcanization of the silicone elastomer.

Utility

The present implant for delivering a hydrophobic active agent andmethods of use thereof find applications where it is desirable toprovide sustained delivery of the active agent locally to a targettissue with reduced side effects, and reduced frequency dosageadministration. For example, the present implant may find use inpreventative intervention for breast cancer. Thus, in some embodiments,an implant of the present disclosure may be loaded with ananti-estrogen, such as fulvestrant, and surgically placed in breasttissue of patients predisposed to or at high risk of developing breastcancer. The exposure to systemic drug and resulting toxicity can besubstantially reduced by localized delivery, increasing compliance. Forfemale patients unwilling to give up their opportunity for conception orhave their breasts removed at a stage in their life, the present implantcould provide the necessary risk reduction until a future point whererisk reduction surgery would be more acceptable. Furthermore, arefillable and reversible tubing as well as the imageable nature of theimplant will allow for dose modification or complete removal and thusenable the plasticity required for adjustment to life events.

In certain embodiments, the present implant finds use in treating cancerby locally delivering a hydrophobic active agent to the canceroustissue. The treatment outcome may include reducing the size of thetumor, slowing the progression of the cancer, and/or eliminating thetumor. In some cases, the cancer is a hormone responsive cancer, such asbreast cancer and prostate cancer. In some cases, the cancer is uterinecancer, brain cancer, skin cancer, ovarian cancer, gastrointestinalcancer, bladder cancer, liver cancer, kidney cancer or pancreaticcancer.

Kits

Also provided herein is a kit that includes the present implant and thatfinds use in performing methods of the present disclosure. The kit mayalso include a packaging that includes a compartment, e.g., a sterilecompartment, for holding the implant. The packaging may be any suitablepackaging for holding the present implant. Examples of implant packagingand methods of packaging an implant are described in, e.g., U.S. Pat.Nos. 3,755,042, 4,482,053, 4,750619; U.S. App. Pub. Nos. 20050268573,20100133133, which are incorporated herein by reference.

In some cases, the implant in the packaging is pre-loaded with an activeagent. In some embodiments, the kit includes one or more of varioussolutions that find use in loading, reloading, or unloading the siliconetubing of the present implant, as described above. The differentcomponents of the kit may be provided in separate containers, asappropriate.

The present kit may also include instructions for using the presentimplant and practicing the present methods. The instructions aregenerally recorded on a suitable recording medium. For example, theinstructions may be printed on a substrate, such as paper or plastic,etc. As such, the instructions may be present in the kits as a packageinsert, in the labeling of the container of the kit or componentsthereof (i.e., associated with the packaging or subpackaging) etc. Inother embodiments, the instructions are present as an electronic storagedata file present on a suitable computer readable storage medium, e.g.CD-ROM, digital versatile disc (DVD), flash drive, Blue-ray Disc™ etc.In yet other embodiments, the actual instructions are not present in thekit, but methods for obtaining the instructions from a remote source,e.g. via the internet, are provided. An example of this embodiment is akit that includes a web address where the instructions can be viewedand/or from which the instructions can be downloaded. As with theinstructions, the methods for obtaining the instructions are recorded ona suitable substrate.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

EXAMPLES

As can be appreciated from the disclosure provided above, the presentdisclosure has a wide variety of applications. Accordingly, thefollowing examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use embodiments of the present disclosure, and are not intendedto limit the scope of what the inventors regard as their invention norare they intended to represent that the experiments below are all or theonly experiments performed. Those of skill in the art will readilyrecognize a variety of noncritical parameters that could be changed ormodified to yield essentially similar results. Efforts have been made toensure accuracy with respect to numbers used (e.g. amounts, dimensions,etc.) but some experimental errors and deviations should be accountedfor.

Example 1: Materials and Methods

General description of materials and methods used in the Examples aredescribed below, unless indicated otherwise.

Preparation of Fulvestrant

Fulvestrant (25 mg) was dissolved in 1.5 mL ethanol under asepticconditions. The resulting solution was 27.4 mM and used for allexperiments described below.

Silastic® Tubing

The Silastic® tubing used was platinum-cured, translucent, Silastic®silicone tubing. This is an FDA approved product.

Drug Loading

Silastic® tubing (0.76 mm I.D., and 1.65 mm O.D.) was cut into 10 cmlength tubes and fulvestrant solution was loaded using a 1 ml tuberculinsyringe with a 20-gauge needle with a void of 1 cm. The tubes were leftto dry for a predetermined time to desiccate, leaving a residue offulvestrant inside the tube. These tubes were sealed with an adhesiveand left to be cured for 48 hours resulting in an inseparable seal, orclipped with titanium ‘Surgiclips™’. The seal was confirmed prior tofurther testing.

Drug Release in Saline

Fulvestrant loaded Silastic® tubing was incubated in saline and rockedat 37° C. Every 84 hours the saline was collected and replaced withfresh saline. The concentration of fulvestrant released in each sampleof saline was determined by liquid chromatography-mass spectrometry (seebelow). Preliminary experiments were conducted using 0.076 mgfulvestrant per 1 cm tubing.

Drug Release in Culture Media

Each sealed (10 cm) tube was immersed into a 10 cm culture tubecontaining 5 mL culture media (Dulbecco's Modified Eagle's medium(DMEM)+10% fetal bovine serum (FBS)+penicillin and streptomycin)approximating interstitial tissue surrounding the breast tissue. Thesetubes were set on a rocker in an incubator at 37° C. for 1, 2, 5, 10,15, 21 and 30 days. After each time point media was collected and storedat −80° C. for further analysis for western blotting,viability/proliferation assay by MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)and quantitation by liquid chromatography-tandem mass spectrometry(LC-MS/MS). Additional iteration was to perform repeated washes on thesame sealed tube and collect the culture medium at days 1, 2, 5, 10, 15,21, and 30.

Results with Collected Media

MCF-7 culture were propagated and seeded in 6 cm dishes at 300,000 cellsper dish and allowed to adhere overnight as a monolayer. On day 0,medium in each dish was replaced with the collected drug medium(described above) that contained fulvestrant elutions of prespecifiedtime periods (1, 2, 5, 10, 15, 21, 30 days, Appropriate referencesamples included drug free medium, and direct administration of 100 nMfulvestrant (control)). The drug concentrations and biological effectsof the drug eluted from specific tubes were evaluated by Massspectroscopy, Western Blot analysis and antiproliferative methods afterexposure for 3 days.

Western Blotting

Cell lysates (described above) were used to evaluate the down-regulationof the estrogen receptor, progesterone receptor and initial attempts forPS2.

MTS Assay

Separate cultures were set in a 96-well format (1000 cells/well) for a3-day exposure to medium collected from the tubes incubated for either1, 2, 5, 10, 15, 21, 30 days along with a set of untreated controls andculture treated with 100 nM fulvestrant. At the end of the exposure,medium was replaced by MTS dye diluted (200 μL per well) in culturemedium and incubated for up to 2 hours at 37° C. Optical density (490nm) at the end of the time points (1, 1.5 and 2 hours) was measure andplotted as a ratio of absorbance (day/untreated).

LC-MS/MS

A validated LC-MS/MS method was used for quantitation of fulvestrant.Sample was prepared by liquid-liquid extraction procedures withn-hexane-isopropanol (90:10, v/v). Extracts were concentrated (using anitrogen stream at room temperature) and derivatized with 2 volumes ofmobile phase buffer, and injected into a Sciex ultra performance liquidchromatorgraphy (UPLC) coupled with a Sciex API 5000™ triple quadrupolemass spectrometer. Data was acquired and analyzed by Analyst® MSsoftware.

In Vivo Assays

Silastic® depot with dry fulvestrant was implanted subcutaneously andadjacent to the inguinal mammary fat pad of CD-1 female mice. Mice weremonitored for body weight loss, activity, adequate grooming, and generalbehavior daily for the first week, followed by alternate days up to 10months. Mice were euthanized and blood and organs were collected after1, 2, 3, 4, 6 and 9 weeks (FIGS. 21 and 22). The level of fulvestrant inblood was determined to ensure estimated fulvestrant level was achieved.Organs were visually examined for overt pathology (e.g. color, size, andgeneral condition) and exhibited none over the 9 week period.

Plasma and Tissue Collection and Processing

Blood from anaesthetized CD-1 female mice were collected in Vacutainer®tubes coated with K₂ ethylenediaminetetraacetic acid (EDTA) via cardiacpuncture. Plasma was separated by centrifugation at 6,000×g for 10minutes and stored at −80° C. Following blood collection, the mammaryfat pads of mice exposed to fulvestrant administration via tubing wereharvested and the amount of fulvestrant taken up by the tissuequantified. Harvested tissue was homogenized in saline on ice and thensubjected to liquid-liquid phase extraction and evaluated for theirlevels of fulvestrant by LC-MS/MS as described above.

Example 2: Use of Silastic® Tubing as a Fulvestrant Depot

Our preliminary data shows that Silastic® tubing is capable of acting asa fulvestrant depot. Silastic® tubing (9 cm, medical grade Rx50 OD 1.65mm, ID 0.76, FIG. 1C) was loaded with dry fulvestrant (0.076 mg/cm) andplaced in tissue culture media for increasing times up to 30 days. Mediacontaining tubing released drug at respective times was then added tocultured MCF7 ER-positive breast cancer cells and grown for 72 hours.Concentration curves of fulvestrant spanning clinically achievableconcentrations of fulvestrant (10-50 nM) and up to a 10 μM wereevaluated for antiproliferative effects at 72 hours showing all theconcentrations were sufficient to block estrogen receptor signaling andproliferation. With an initial delay, as expected by the Silastic® tubekinetics, drug transfer for fulvestrant from the tubing was comparableto 100 nM of fulvestrant directly added to the culture media. Tubeequilibration was sufficient within 2-5 days to achieve growthinhibition and estrogen receptor down regulation comparable to cellsdirectly treated with fulvestrant (100 nM) (FIG. 16, panels A and B).Daily washout experiments further demonstrate that drug release from theSilastic® tubing for each 24-hour period is comparable and is sustainedfor at least 28 days. Weekly fulvestrant release was also consistent formore than 4 weeks in cell culture models, as measured by ER and PR downregulation (inset in FIG. 16, panel B), up to and beyond 12 weeks (FIGS.17 and 18). Further data showed that this approach is amenable to drugtransfer for raloxifene, 4-hydroxytamoxifen and estradiol (see Example5).

FIG. 16, panels A-B: Silastic® tubing (9 cm) was loaded with 0.68 mgfulvestrant and incubated in 5 mL medium at 37° C. for the indicatedtime (Panel A) or harvested every 24 hours and replenished with freshand replenished with fresh medium (Panel B). The medium was then used toculture MCF7 cells for 72 h, and the cells were assayed forproliferation by MTS assay (Panel A) and harvested for protein andwestern blotted for ER and PR expression (Panel B). Inset in Panel Bdemonstrates sufficient fulvestrant release to inhibit ER and PRexpression for at least 28 days. As a positive control, MCF7 cells weretreated directly with 100 nM fulvestrant (last bar in Panel A), aconcentration sufficient to down regulate ER expression and arrest cellgrowth.

FIG. 17: Fulvestrant released from Silastic® implant was sufficient toinhibit target (e.g. estrogen receptor (ER)) in breast cancer cells(MCF7) up to 12 weeks. Controls included untreated MCF7 breast cancercells (−) and MCF7 breast cancer cells treated with a clinicallyachievable dose (100 nM) of fulvestrant (+).

FIG. 18: Fulvestrant released from the Silastic® tubing sustainsdown-regulation of ER expression in MCF7 and T47D cells beyond 12 weeks.As negative controls, the cells were untreated or treated with mediaincubated with ethanol-loaded tubing. As a positive control, the cellswere directly treated with 100 nM fulvestrant.

Release of fulvestrant from loaded Silastic® tubing into culture medium,as described above, was measured using LC-MS/MS and was sustained for upto 22 weeks (FIG. 19).

FIG. 19: Fulvestrant released from the Silastic® tubing in culturemedium. Media was harvested semi-weekly (84 hrs).

Release of fulvestrant from loaded Silastic® tubing into a salinesolution was measured using LC-MS/MS (FIG. 20). After 5 weeks, the rateof fulvestrant released remained steady with an average of 7.77 ng/cmtubing*day, exceeding 7 months. Based on this rate of release and theamount of fulvestrant in the device, the extrapolated duration ofrelease exceeds 10 years.

FIG. 20: Four Silastic® devices were loaded with fulvestrant andimmersed in saline and continuously rocked at 37 C. Every 84 hours,saline was collected and replaced with fresh saline. Fulvestrant wasquantified in collected saline by liquid chromatography massspectrometry.

Example 3: Localized and Sustained Release of Fulvestrant in MammaryTissue

FIG. 21: A silastic device containing fulvestrant was implanted intofemale mice (CD-1) adjacent to their inguinal mammary tissue. The micewere implanted with 2 cm RX50 silastic tubing containing 0.076 mg/cm dryfulvestrant adjacent to the inguinal mammary fat pad. After theindicated number of weeks the mice were euthanized and tissue washarvested. The concentration of fulvestrant was measured in the bloodand mammary tissue of 4 mice using liquid chromatography massspectrometry.

In all but one mouse at week 4, fulvestrant was undetectable in blood(<4 nM; Table 1 in FIG. 22), whereas significant fulvestrant wasdetectable in the mammary tissue of all mice.

Example 4: Use of Silastic® Tubing as an Estradiol Depot

The effect of estradiol released from Silastic® tubing loaded withestradiol and placed in culture medium was monitored, using conditionssimilar to that described in Example 2. Sustained increased inprogesterone receptor (PgR) mRNA expression was observed for up to 15days (FIG. 23).

FIG. 23: Drug (E2) was loaded into 3 independent silastic tubes, dried,and sealed before incubating them in tissue culture medium for theindicated number of days. The tubes were then removed and MCF7 cellswere treated with the medium. For the E2 experiment, MCF7 cells werefirst depleted of E2 by growing for 48 hours in FBS stripped media.Then, after 24 hours of treatment with media containing released E2,cells were harvested and progesterone receptor mRNA was quantified byquantitative real-time (qRT)-polymerase chain reaction (PCR) usingTaqMan® probes from Applied Biosystems. As controls, MCF7 cellsuntreated and treated directly with 10 nM E2 were run.

Example 5: Formulation of Fulvestrant Loaded Silastic® Tubing

Two key aspects of formulation are solubility and stability. Fulvestrantis a highly lipophilic compound that precludes its formulation inaqueous based excipients. For clinical use, fulvestrant has beendeveloped as a long acting (˜1 month) intramuscular formulation(Faslodex®, AstraZeneca Pharmaceuticals), by solubilizing up to 50 mg/mLin 10% ethanol, 10% benzyl alcohol, 15% benzyl benzoate, and to 100%with castor oil. Additional formulations have been developed thatexhibit stability and comparable to or greater then solubilityconcentrations achieved with the Faslodex® formulation. Theseformulations use combinations of organic solvents, glycofurol,dihydrolipoic acid, and poloxamers. In addition to dry powder andFaslodex® fulvestrant formulations, three additional formulations areevaluated: (1) 50% glycofurol/50% propylene glycol (200 mg/mL), (2) 50%glycofurol/50% polyethylene glycol 400 (200 mg/mL), and (3) 20 mgLutrol® in dihydrolipoic acid (350 mg/mL). Thus, in total, fivefulvestrant formulations are compred as described below. For eachformulation, PK parameters including Cmax, Tmax, Elimination Rate,Half-life and AUC (Area_under_Curve) over-time are estimated withdescriptive statistics for comparison.

Example 6: Evaluation of Anti-Estrogen Implant in an In Vivo Goat Model

To evaluate the effectiveness of the Silastic® anti-estrogen implant ina large animal model mimicking the human female mammary system andanatomy, female alpine goats are used. Using the alpine goat model, theimplant are tested for: 1) feasibility for surgical subglandularplacement, 2) directional delivery of fulvestrant distal into mammarytissue, 3) the concentration and diffusion of fulvestrant throughmammary tissue overtime, 4) the biodistribution of released fulvestrantin major organs and blood, 5) fibrotic capsule formation in proximity tothe implant, and 6) resultant organ pathology and toxicity. These sixoutcomes are evaluated by surgically implanting a single device (10 cmin diameter containing 5 meters of silastic tubing loaded with 0.076mg/cm tubing of fulvestrant) in the subglandular region of the udder in3 female alpine goats. Every 7 days, blood and a mammary tissue biopsyare collected and evaluated for fulvestrant concentration. On day 28,the goats are sacrificed and organs are examined for overt pathology.Major organs, blood, and mammary tissue are collected and fulvestrantconcentration is determined in each. Additionally, a blood chemistrypanel and complete blood count are conducted at study initiation andconclusion to assess potential toxicity. Diffusion of fulvestrantthrough breast tissue is measured by sampling tissue at intermediatedistances distally from the implant to the udder nipple during eachbiopsy. Implant and surrounding tissue are collected together at theconclusion of the study and are evaluated for fibrotic capsule formationby immunohistochemical analysis.

Example 7: Determining the Efficacy of Fulvestrant Released fromSilastic® Tubing to Prevent Tumor Formation

2 cohorts of 15 4-6 weeks old female nude athymic Crl;NU(NCr)-Foxn1^(nu)mice, totaling 30 mice, are implanted with 5×10⁶ breast cancer cells(1:1 v/v with Matrigel™) in the inguinal mammary fat pad. Two days priorto tumor cell implantation, a 60-day release estrogen pellet isimplanted subcutaneously in the flank of each mouse. Cohort 1 isimplanted with 4 cm of Silastic® tubing loaded with vehicle. Cohort 2 isimplanted with 4 cm of Silastic® tubing loaded with formulatedfulvestrant. For both cohorts 1 and 2, Silastic® tubing is placed in thesubcutaneous space proximal to the inguinal fat pad cell implantation 5days prior to cell implantation. Tumor volumes, by caliper measurement,and weights are assessed three times weekly. Animals are monitored dailyfor toxicity and are euthanized if tumors exceed 1.5 cm in its largestdiameter, total volume exceeds 2000 mm³, or when mice exhibit pain ordistress.

Preliminary work has shown that fulvestrant released from Silastic®tubing is sufficient to abrogate ER signaling and reduce cellproliferation of MCF7 cells in vitro. To determine whether thesepharmacodynamic effects extend to tumors in vivo, tumors are harvestedimmediately post euthanasia and divided into four parts for protein,RNA, immunohistochemical analysis, and fulvestrant extraction. Eachtechnique are evaluated for expression of ER, ER response genes, and keyproliferative genes/proteins including PgR, cyclin D1 and E, pS2, EBAG9,p21, p27, c-Myc, and Ki-67. As described above, concentrations offulvestrant in plasma, organs and tumor tissue are determined byLC-MS/MS. The fulvestrant released from Silastic® tubing is dichotomizedinto two groups as low and high based on the median (or from theobserved cutpoint of the data distribution). The expression of ER, ERresponse genes and key proliferative genes/proteins expression iscompared between the dichotomized fulvestrant groups. T-test is used forthe mean difference of each expression between groups.

While embodiments of the present disclosure has been described withreference to the specific embodiments thereof, it should be understoodby those skilled in the art that various changes may be made andequivalents may be substituted without departing from the true spiritand scope of the disclosure. In addition, many modifications may be madeto adapt a particular situation, material, composition of matter,process, process step or steps, to the objective, spirit and scope ofthe present disclosure. All such modifications are intended to be withinthe scope of the claims appended hereto.

What is claimed is:
 1. A method of treating prostate cancer in asubject, the method comprising: implanting a depot in a prostate in saidsubject, wherein said depot comprises, prior to said implanting: abiocompatible tubing having a wall devoid of any through-hole, first andsecond opposed ends formed from a portion of the wall of thebiocompatible tubing, a lumen extending between the first and secondopposed ends and defining a fully enclosed volume, said first and secondopposed ends being sealed; and a hormone-modulating active agentprovided in the fully enclosed volume, wherein said biocompatible tubingis permeable to said hormone-modulating active agent and the only meansfor the hormone-modulating active agent to exit the fully enclosedvolume is by diffusing through the wall of the biocompatible tubingincluding the portion of the wall forming the first and second opposedends that are sealed, the depot delivering said hormone-modulatingactive agent to said prostate in said subject as said hormone-modulatingactive agent is released through said wall including the portion of thewall forming the first and second opposed ends of said biocompatibletubing when implanted in said prostate in said subject.
 2. The method ofclaim 1, wherein said depot is an elastomeric silicone tubing.
 3. Themethod of claim 1, wherein said hormone-modulating active agent isselected from the group consisting of a cholesterol, an estradiol, aprogesterone, a testosterone, a corticosteroid, derivatives thereof, andsynthetic analogs thereof.
 4. The method of claim 1, wherein saidhormone-modulating active agent is present in said depot at aconcentration of about 0.0001 mg to about 10 mg per cm of the depot. 5.The method of claim 1, wherein said delivery of said hormone-modulatingactive agent to said prostate is at an average level of about 50 nM toabout 1000 nM of said hormone-modulating active agent in said prostate.6. The method of claim 1, wherein a level of said hormone-modulatingactive agent in blood plasma is about 95% or less when compared to alevel of said hormone-modulating active agent in said prostate.
 7. Themethod of claim 1, wherein said hormone-modulating active agent ispresent in a non-target tissue from a substantially undetectable levelto about 10 nM.
 8. The method of claim 1, wherein said depot isconfigured to deliver said hormone-modulating active agent to saidprostate for about 5 weeks to about 10 years.
 9. The method of claim 1,wherein the biocompatible tubing has an intertwined, double-helicalform.
 10. The method of claim 1, further comprising a fill port attachedto the biocompatible tubing.
 11. The method of claim 1, wherein saidhormone-modulating active agent is selected from the group consisting ofan anti-estrogen, an anti-androgen, a selective estrogen receptormodulator (SERM), and a selective estrogen receptor down-regulator. 12.A method of modulating hormone levels in a target tissue in a subject,the method comprising: implanting a polymeric tubing in said targettissue, wherein said polymeric tubing comprises, prior to saidimplanting: first and second ends; a lumen extending between the firstand second ends; a polymeric wall extending between the first and secondends, the polymeric wall fully surrounding the lumen and defining afully enclosed volume; and an active agent distributed throughout saidpolymeric wall, wherein said polymeric wall is permeable to said activeagent, and the first and second ends are sealed such that the only meansfor the active agent to exit the polymeric tubing is by diffusingthrough the polymeric wall; and the polymeric tubing directly deliveringsaid active agent to said target tissue in said subject as said activeagent is released through said polymeric wall of said polymeric tubingwhen implanted in said target tissue.
 13. The method of claim 12,wherein said active agent is a steroid.
 14. The method of claim 12,wherein said active agent lowers androgen levels.
 15. The method ofclaim 12, wherein said active agent is selected from the groupconsisting of an anti-estrogen, an anti-androgen, a selective estrogenreceptor modulator (SERM), a selective estrogen receptor down-regulator,and an inhibitor of poly adenosine diphosphate (ADP) ribose polymerase(PARP).
 16. The method of claim 12, wherein said polymeric tubing isfabricated from a non-biodegradable material.
 17. The method of claim12, wherein said target tissue comprises a breast tissue or a prostatetissue.
 18. The method of claim 12, wherein said active agent is presentin said polymeric tubing at a concentration of about 0.0001 mg to about10 mg per cm of the polymeric tubing.
 19. The method of claim 12,wherein after said implanting, an average level of said active agent insaid target tissue is in a range of about 50 nM to about 1000 nM. 20.The method of claim 12, wherein said active agent is present in anon-target tissue from a substantially undetectable level to about 10nM.
 21. The method of claim 12, wherein said polymeric tubing delivers asustained release of said active agent to said target tissue.
 22. Themethod of claim 12, wherein said polymeric tubing delivers said activeagent to said tissue for about 5 weeks to about 10 years.
 23. The methodof claim 12, wherein said polymeric wall comprises a polymer matrix andwherein said active agent is distributed throughout said polymer matrix.24. The method of claim 12, wherein the active agent is hydrophobic andthe polymeric wall is permeable to the hydrophobic active agent.
 25. Themethod of claim 12, wherein the polymeric tubing has an intertwined,double-helical form.